HRP20150030T1 - Pyrazoloquinoline derivatives as dna-pk inhibitors - Google Patents

Pyrazoloquinoline derivatives as dna-pk inhibitors Download PDF

Info

Publication number
HRP20150030T1
HRP20150030T1 HRP20150030AT HRP20150030T HRP20150030T1 HR P20150030 T1 HRP20150030 T1 HR P20150030T1 HR P20150030A T HRP20150030A T HR P20150030AT HR P20150030 T HRP20150030 T HR P20150030T HR P20150030 T1 HRP20150030 T1 HR P20150030T1
Authority
HR
Croatia
Prior art keywords
image
alk
hal
formula
compounds
Prior art date
Application number
HRP20150030AT
Other languages
Croatian (hr)
Inventor
Thomas Fuchss
Werner Mederski
Frank Zenke
Original Assignee
Merck Patent Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Publication of HRP20150030T1 publication Critical patent/HRP20150030T1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/99—Enzyme inactivation by chemical treatment

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Genetics & Genomics (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Oncology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)

Claims (15)

1. Spojevi formule (I) [image] naznačeni time da R1 označava Y, -Alk-OY, -Alk-NYY ili -Alk-Ar, R2 označava Y, -Alk-OY, -Alk-NYY, -C(Y)(R6)(R7), -C(Hal)(R6)(R7), -SO2A, -SO2-Ar ili -POOH-Ar, R3 označava H, Hal, CN, -Alk-CN, -Alk-NYY, Het1 ili Het2, R4 označava Hal, Y, Cyc, CN, -Alk-CN, -Alk-COOY, -Alk-CO-NYY ili Het1, R5 označava Hal, Y, OY, NYY, -NY-COY, COOY, -CO-NYY, -CO-NY-Alk-OY, -Alk-CO-NYY, -Alk-OY, -Alk-NYY, Ar, Het1 ili Het2, R3, R5 zajedno također označavaju -Alk-CO-NY, R6 označava Hal, Y, -COOY, -CO-NYY, -CO-NY-OY, -CO-NY-C(=NH)-NYY, -CO-NY-Alk-OY, -CO-NY-Alk-NYY, -CO-NY-Alk-SO2-NYY, -CO-NY-Alk-Ar, -CO-NY-Alk-Het2 ili -CO-NY-O-Alk-CN, R7 označava Ar, Het1 ili -Het1-Het1, X označava CH2, O, S ili Het1, Y označava H ili A, A označava nerazgranati ili razgranati alkil koji ima 1-10 C atoma, gdje, međusobno neovisno, 1-7 H atoma može biti zamijenjeno sa Hal i/ili, međusobno neovisno, jedna ili dvije susjedne CH2 skupine mogu biti zamijenjene sa -CH=CH- i/ili -CΞC- skupinom, Alk označava alkilen koji ima 1-6 C atoma, gdje, međusobno neovisno, 1-4 H atoma može biti zamijenjeno sa Hal i/ili OY, Cyc označava ciklički alkil koji ima 3-7 C atoma, gdje, međusobno neovisno, 1-4 H atoma može biti zamijenjeno sa Hal i/ili OY, Ar označava fenil koji je nesupstituiran ili monosupstituiran sa Hal, A, CN, OY, NYY, -NY-COY, COOY, Het1, Het2, -Alk-OY, -Alk-NYY, -Alk-Het1 ili Alk-Het2, Het1 označava mono- ili biciklički heteroaril koji ima 2-9 C atoma i 1-4 N, O i/ili S atoma, koji mogu biti nesupstituirani ili monosupstituirani sa Hal, A, CN, OY, NYY, -NY-COY, COOY, -Alk-OY ili -Alk-NYY, Het2 označava monociklički zasićeni heterocikal koji ima 2-7 C atoma i 1-4 N, O i/ili S atoma, koji mogu biti nesupstituirani ili monosupstituirani sa A, te Hal označava F, Cl, Br ili I, i/ili fiziološki prihvatljive soli, tautomeri i/ili njihovi stereoizomeri, uključujući njihove smjese u svim omjerima.1. Compounds of formula (I) [image] indicated that R1 denotes Y, -Alk-OY, -Alk-NYY or -Alk-Ar, R2 denotes Y, -Alk-OY, -Alk-NYY, -C(Y)(R6)(R7), -C(Hal)(R6)(R7), -SO2A, -SO2-Ar or -POOH-Ar , R3 denotes H, Hal, CN, -Alk-CN, -Alk-NYY, Het1 or Het2, R4 denotes Hal, Y, Cyc, CN, -Alk-CN, -Alk-COOY, -Alk-CO-NYY or Het1, R5 represents Hal, Y, OY, NYY, -NY-COY, COOY, -CO-NYY, -CO-NY-Alk-OY, -Alk-CO-NYY, -Alk-OY, -Alk-NYY, Ar, Het1 or Het2, R3, R5 together also denote -Alk-CO-NY, R 6 stands for Hal, Y, -COOY, -CO-NYY, -CO-NY-OY, -CO-NY-C(=NH)-NYY, -CO-NY-Alk-OY, -CO-NY-Alk- NYY, -CO-NY-Alk-SO2-NYY, -CO-NY-Alk-Ar, -CO-NY-Alk-Het2 or -CO-NY-O-Alk-CN, R7 denotes Ar, Het1 or -Het1-Het1, X stands for CH2, O, S or Het1, Y stands for H or A, A denotes unbranched or branched alkyl having 1-10 C atoms, where, independently of each other, 1-7 H atoms can be replaced by Hal and/or, independently of each other, one or two adjacent CH2 groups can be replaced by -CH=CH - and/or -CΞC- group, Alk denotes alkylene having 1-6 C atoms, where, independently of each other, 1-4 H atoms can be replaced by Hal and/or OY, Cyc denotes a cyclic alkyl having 3-7 C atoms, where, independently of each other, 1-4 H atoms can be replaced by Hal and/or OY, Ar denotes phenyl which is unsubstituted or monosubstituted by Hal, A, CN, OY, NYY, -NY-COY, COOY, Het1, Het2, -Alk-OY, -Alk-NYY, -Alk-Het1 or Alk-Het2, Het1 denotes mono- or bicyclic heteroaryl having 2-9 C atoms and 1-4 N, O and/or S atoms, which may be unsubstituted or monosubstituted with Hal, A, CN, OY, NYY, -NY-COY, COOY , -Alk-OY or -Alk-NYY, Het2 denotes a monocyclic saturated heterocycle having 2-7 C atoms and 1-4 N, O and/or S atoms, which may be unsubstituted or monosubstituted with A, and Hal stands for F, Cl, Br or I, and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including their mixtures in all proportions. 2. Spojevi prema zahtjevu 1 koji imaju djelomičnu formulu (IA) [image] naznačeni time da R1, R4 označavaju Y, R2 označava Y ili -CH(R6)(R7), R5 označava Hal, Y, COOY, Alk-OA ili Het2, R6 označava -CO-NYY, -CO-NY-OY, -CO-NY-C(=NH)-NYY ili -CO-NY-Alk-OY, R7 označava Ar ili Het1, Y označava H ili A, A označava nerazgranati ili razgranati alkil koji ima 1-4 C atoma, gdje, međusobno neovisno, 1-3 H atoma može biti zamijenjeno sa Hal, Alk označava alkilen koji ima 1-3 C atoma, gdje 1-2 H atoma mogu biti zamijenjeni sa Hal i/ili OH, Ar označava fenil koji je nesupstituiran ili monosupstituiran sa Hal, Het1 označava mono- ili biciklički heteroaril koji ima 2-9 C atoma i 1-3 N i/ili S atoma, koji mogu biti nesupstituirani ili monosupstituirani sa Hal, A, CN ili NYY, Het2 označava monociklički zasićeni heterocikal koji ima 3-5 C atoma i 1-2 N i/ili O atoma, koji mogu biti nesupstituirani ili monosupstituirani sa A, te Hal označava F, Cl, Br ili I, i/ili fiziološki prihvatljive soli, tautomeri i/ili njihovi stereoizomeri, uključujući njihove smjese u svim omjerima.2. Compounds according to claim 1 having the partial formula (IA) [image] indicated that R1, R4 denote Y, R2 denotes Y or -CH(R6)(R7), R5 denotes Hal, Y, COOY, Alk-OA or Het2, R6 denotes -CO-NYY, -CO-NY-OY, -CO-NY-C(=NH)-NYY or -CO-NY-Alk-OY, R7 denotes Ar or Het1, Y stands for H or A, A denotes unbranched or branched alkyl having 1-4 C atoms, where, independently of each other, 1-3 H atoms can be replaced by Hal, Alk means alkylene having 1-3 C atoms, where 1-2 H atoms can be replaced by Hal and/or OH, Ar denotes phenyl which is unsubstituted or monosubstituted with Hal, Het1 denotes mono- or bicyclic heteroaryl having 2-9 C atoms and 1-3 N and/or S atoms, which may be unsubstituted or monosubstituted with Hal, A, CN or NYY, Het2 denotes a monocyclic saturated heterocycle having 3-5 C atoms and 1-2 N and/or O atoms, which may be unsubstituted or monosubstituted with A, and Hal stands for F, Cl, Br or I, and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including their mixtures in all proportions. 3. Spojevi prema zahtjevu 1 ili 2, naznačeni time da su odabrani iz skupine: [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] i/ili fiziološki prihvatljive soli, tautomeri i/ili njihovi stereoizomeri, uključujući njihove smjese u svim omjerima.3. Compounds according to claim 1 or 2, characterized in that they are selected from the group: [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including their mixtures in all proportions. 4. Međuprodukti spojeva formule (II) [image] u kojoj R8 označava CN ili =O, i R9 označava NO2 ili NYY, i R1, R2, R5 i Y imaju značenje navedeno u zahtjevu 1, i/ili soli, tautomeri i/ili njihovi stereoizomeri, uključujući njihove smjese u svim omjerima.4. Intermediate products of compounds of formula (II) [image] where R 8 represents CN or =O, i R9 represents NO2 or NYY, and R1, R2, R5 and Y have the meaning specified in claim 1, and/or salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all proportions. 5. Međuprodukti spojeva prema zahtjevu 4 koji imaju djelomičnu formulu (IIA) [image] naznačeni time da R1, R2, međusobno neovisno, označavaju A ili -Alk-Ar, i Alk označava alkilen koji ima 1-3 C atoma, gdje 1-2 H atoma može biti zamijenjeno sa Hal, i R5, A, Ar i Hal imaju značenje navedeno u zahtjevu 2, i/ili soli, tautomeri i/ili njihovi stereoizomeri, uključujući njihove smjese u svim omjerima.5. Intermediates of compounds according to claim 4 having the partial formula (IIA) [image] indicated that R1, R2, independently of each other, denote A or -Alk-Ar, i Alk denotes an alkylene having 1-3 C atoms, where 1-2 H atoms may be replaced by Hal, and R5, A, Ar and Hal have the meaning specified in claim 2, and/or salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all proportions. 6. Međuprodukti spojeva formule (III) [image] naznačeni time da R10 označava H ili Hal, i R1, R2, R4 i Hal imaju značenje navedeno u zahtjevu 1, i/ili soli, tautomeri i/ili njihovi stereoizomeri, uključujući njihove smjese u svim omjerima.6. Intermediate products of compounds of formula (III) [image] indicated that R 10 denotes H or Hal, and R1, R2, R4 and Hal have the meaning specified in claim 1, and/or salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all proportions. 7. Međuprodukti spojeva prema zahtjevu 6 naznačeni time da R1, R2, međusobno neovisno, označavaju A ili -Alk-Ar, R10 označava Hal, i Alk označava alkilen koji ima 1-3 C atoma, gdje 1-2 H atoma mogu biti zamijenjeni sa Hal, i R4, A, Ar i Hal imaju značenje navedeno u zahtjevu 2, i/ili fiziološki prihvatljive soli, tautomeri i/ili njihovi stereoizomeri, uključujući njihove smjese u svim omjerima.7. Intermediates of compounds according to claim 6, characterized in that R1, R2, independently of each other, denote A or -Alk-Ar, R 10 stands for Hal, and Alk denotes an alkylene having 1-3 C atoms, where 1-2 H atoms may be replaced by Hal, and R4, A, Ar and Hal have the meaning specified in claim 2, and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including their mixtures in all proportions. 8. Postupak za pripravu spojeva formule (I) prema zahtjevu 1, njihovih djelomičnih formula i/ili fiziološki prihvatljivih soli, tautomera i/ili njihovih stereoizomeri, uključujući njihove smjese u svim omjerima, koji sadrži slijedeće korake: (a) reakciju spoja djelomične formule (IIA) [image] u kojoj R1, R2 i R5 imaju značenje navedeno u zahtjevu 5, u kiselom mediju s redukcijskim sredstvom i sa spojem E-NO2, u kojem E označava element iz prve glavne skupine, da se dobiju spojevi djelomične formule (IB) [image] u kojoj R1, R2 i R5 imaju značenje navedeno u zahtjevu 5, i proizvoljno (b') reakciju spojeva djelomične formule (IB) sa spojem Hal-R4, u kojem R4 i Hal imaju značenje navedeno u zahtjevu 1, da se dobiju spojevi djelomične formule (IC) [image] u kojoj R1, R2 i R5 imaju značenje navedeno u zahtjevu 5, i R4 ima značenje navedeno u zahtjevu 1, (b") pretvorbu R1, -O-R2, R4, R5 i/ili CN skupine spojeva djelomične formule (IC) da se dobiju spojevi djelomične formule (IE) [image] u kojoj R1, R2, R3, R4, R5 i X imaju značenje navedeno u zahtjevu 1, i/ili (b"') pretvorbu baze ili kiseline spojeva djelomične formule (IE) ili djelomične formule (IB) ili (IC) u jednu od njihovih fiziološki prihvatljivih soli, ili (a) reakciju spoja s formulom (III) [image] u kojoj R1, R2, R4 i R10 imaju značenje navedeno u zahtjevu 7, sa spojem s formulom (IV) [image] u kojoj D označava bornu kiselinu, borni ester, organokositreni spoj ili borni trifluorometansulfonat, te R3 i R5 imaju značenje navedeno u zahtjevu 1, da se dobiju spojevi djelomične formule (ID) [image] u kojoj R1, R2 i R4 imaju značenje navedeno u zahtjevu 7, i R3 i R5 imaju značenje navedeno u zahtjevu 1, te proizvoljno (b') pretvorbu R1, -O-R2, R3, R4 i/ili R5 spojeva djelomične formule (ID) da se dobiju spojevi formule (I) [image] u kojoj R1, R2, R3, R4, R5 i X imaju značenje navedeno u zahtjevu 1, i/ili (b") pretvorbu baze ili kiseline spojeva formule (I) ili djelomične formule (ID) u jednu od njihovih fiziološki prihvatljivih soli.8. Process for the preparation of compounds of formula (I) according to claim 1, their partial formulas and/or physiologically acceptable salts, tautomers and/or their stereoisomers, including their mixtures in all proportions, which contains the following steps: (a) reaction of the compound of partial formula (IIA) [image] in which R1, R2 and R5 have the meaning specified in claim 5, in an acidic medium with a reducing agent and with the compound E-NO2, where E denotes an element from the first main group, to obtain compounds of partial formula (IB) [image] in which R1, R2 and R5 have the meaning specified in claim 5, and arbitrary (b') the reaction of compounds of partial formula (IB) with the compound Hal-R4, in which R4 and Hal have the meaning specified in claim 1, to obtain compounds of partial formula (IC) [image] wherein R1, R2 and R5 have the meaning given in claim 5, and R4 has the meaning given in claim 1, (b") conversion of R1, -O-R2, R4, R5 and/or CN group of compounds of partial formula (IC) to obtain compounds of partial formula (IE) [image] in which R1, R2, R3, R4, R5 and X have the meaning specified in claim 1, and/or (b"') converting the base or acid of compounds of partial formula (IE) or partial formula (IB) or (IC) into one of their physiologically acceptable salts, or (a) reaction of the compound of formula (III) [image] in which R1, R2, R4 and R10 have the meaning specified in claim 7, with a compound of formula (IV) [image] where D denotes boric acid, boronic ester, organotin compound or boronic trifluoromethanesulfonate, and R3 and R5 have the meaning specified in claim 1, to obtain compounds of partial formula (ID) [image] in which R1, R2 and R4 have the meaning given in claim 7, and R3 and R5 have the meaning given in claim 1, and arbitrary (b') conversion of R 1 , -O-R 2 , R 3 , R 4 and/or R 5 of compounds of partial formula (ID) to obtain compounds of formula (I) [image] in which R1, R2, R3, R4, R5 and X have the meaning specified in claim 1, and/or (b") converting the base or acid of the compounds of formula (I) or partial formula (ID) into one of their physiologically acceptable salts. 9. Postupak za pripravu međuprodukta spojeva formule (II) prema zahtjevu 4 i/ili soli, tautomera i/ili njihovih stereoizomera, uključujući njihove smjese u svim omjerima, koji sadrži slijedeće korake: (a) reakciju spoja s formulom (V) [image] u kojoj Hal označava F, Cl, Br ili I, i R1, R2 i R9 imaju značenje navedeno u zahtjevu 4, sa spojem s formulom (VI) [image] u kojoj R5 i R8 imaju značenje navedeno u zahtjevu 4, da se dobiju spojevi formule (II) [image] u kojoj R1, R2, R5, R8 i R9 imaju značenje navedeno u zahtjevu 4, i proizvoljno (b) pretvorbu baze ili kiseline spojeva formule (II) u jednu od njezinih soli.9. Process for the preparation of intermediate compounds of formula (II) according to claim 4 and/or salts, tautomers and/or their stereoisomers, including their mixtures in all proportions, which contains the following steps: (a) reaction of the compound of formula (V) [image] where Hal stands for F, Cl, Br or I, and R1, R2 and R9 have the meaning specified in claim 4, with a compound of formula (VI) [image] in which R5 and R8 have the meaning specified in claim 4, to obtain compounds of formula (II) [image] in which R1, R2, R5, R8 and R9 have the meaning specified in claim 4, and arbitrary (b) converting the base or acid of the compounds of formula (II) into one of its salts. 10. Postupak za pripravu međuprodukta spojeva formule (III) prema zahtjevu 6, njihovih djelomičnih formula i/ili soli, tautomera i/ili njihovih stereoizomera, uključujući njihove smjese u svim omjerima, koji sadrži slijedeće korake: (a) reakciju spoja s formulom (VII) [image] u kojoj R1 i R2 imaju značenje navedeno u zahtjevu 6, u kiselom mediju sa spojem E-NO2, u kojem E označava element iz prve glavne skupine, da se dobiju spojevi djelomične formule (IIIA) [image] u kojoj R1 i R2 imaju značenje navedeno u zahtjevu 6, te proizvoljno (b') halogeniranje spojeva djelomične formule (IIIA) da se dobiju spojevi djelomične formule (IIIB) [image] u kojoj R1, R2 i Hal imaju značenje navedeno u zahtjevu 6, (b") reakciju spojeva s formulom (IIIA) ili (IIIB) sa spojem Hal-R4, u kojem R4 i Hal imaju značenje navedeno u zahtjevu 6, da se dobiju spojevi formule (III) [image] u kojoj R1, R2, R4 i R10 imaju značenje navedeno u zahtjevu 6, i/ili (b'") pretvorbu baze ili kiseline spojeva formule (III) u jednu od njezinih soli.10. Process for the preparation of intermediate compounds of formula (III) according to claim 6, their partial formulas and/or salts, tautomers and/or their stereoisomers, including their mixtures in all proportions, which contains the following steps: (a) reaction of the compound of formula (VII) [image] in which R1 and R2 have the meaning specified in claim 6, in an acidic medium with the compound E-NO2, where E denotes an element from the first main group, to obtain compounds of partial formula (IIIA) [image] in which R1 and R2 have the meaning specified in claim 6, and arbitrary (b') halogenation of compounds of partial formula (IIIA) to give compounds of partial formula (IIIB) [image] in which R1, R2 and Hal have the meaning specified in claim 6, (b") reaction of compounds with the formula (IIIA) or (IIIB) with the compound Hal-R4, in which R4 and Hal have the meaning specified in claim 6, to obtain compounds of formula (III) [image] in which R1, R2, R4 and R10 have the meaning specified in claim 6, and/or (b'") conversion of the base or acid of the compounds of formula (III) into one of its salts. 11. Uporaba spojeva prema jednom zahtjevu od 1 do 3 i/ili fiziološki prihvatljivih soli, tautomera i/ili njihovih stereoizomera, uključujući njihove smjese u svim omjerima, naznačena time da je za pripravu medikamenta za inhibiciju serin/treonin protein kinaza, poželjno PIKK, naročito poželjno DNA-PK.11. The use of compounds according to one claim from 1 to 3 and/or physiologically acceptable salts, tautomers and/or their stereoisomers, including their mixtures in all proportions, indicated that for the preparation of medication for the inhibition of serine/threonine protein kinases, preferably PIKK, especially preferably DNA-PK. 12. Uporaba barem jednog spoja prema jednom zahtjevu od 1 do 3 i/ili fizioloških prihvatljivih soli, tautomera i/ili njihovih stereoizomera, uključujući njihove smjese u svim omjerima, naznačena time da je za senzibilizaciju stanica raka u antikancerogenim sredstvima i/ili ionizirajućem zračenju, uz uvjet da se senzibilizacija ne odvija in vivo na ljudskom ili životinjskom tijelu.12. The use of at least one compound according to one claim from 1 to 3 and/or physiologically acceptable salts, tautomers and/or their stereoisomers, including their mixtures in all proportions, indicated that it is for the sensitization of cancer cells in anticancer agents and/or ionizing radiation , provided that the sensitization does not take place in vivo on the human or animal body. 13. Medikament naznačen time da sadrži barem jedan spoj prema jednom zahtjevu od 1 do 3 i/ili fiziološki prihvatljive soli, tautomeri i/ili njihovi stereoizomeri, uključujući njihove smjese u svim omjerima.13. Medicinal product characterized by the fact that it contains at least one compound according to one claim from 1 to 3 and/or physiologically acceptable salts, tautomers and/or their stereoisomers, including their mixtures in all proportions. 14. Farmaceutski pripravak naznačen time da sadrži, kao aktivni spoj, učinkovitu količinu barem jednog spoja prema jednom zahtjevu od 1 do 3 i/ili fiziološki prihvatljivih soli, tautomera i/ili njihovih stereoizomera, uključujući njihove smjese u svim omjerima, zajedno s farmaceutski podnošljivim pomoćnim sredstvima, u kombinaciji s barem jednim antikancerogenim sredstvom.14. Pharmaceutical preparation characterized in that it contains, as an active compound, an effective amount of at least one compound according to one claim from 1 to 3 and/or physiologically acceptable salts, tautomers and/or their stereoisomers, including their mixtures in all proportions, together with pharmaceutically acceptable auxiliary means, in combination with at least one anticancer agent. 15. Spojevi prema jednom zahtjevu od 1 do 3 i/ili fiziološki prihvatljive soli, tautomeri i/ili njihovi stereoizomeri, uključujući njihove smjese u svim omjerima, naznačeni time da su za profilaksu, terapiju i/ili kontrolu napredovanja raka, tumora, metastaza i/ili poremećaja angiogeneze, u kombinaciji s radioterapijom i/ili s najmanje jednim antikancerogenim sredstvom.15. Compounds according to one claim from 1 to 3 and/or physiologically acceptable salts, tautomers and/or their stereoisomers, including their mixtures in all proportions, indicated that they are for prophylaxis, therapy and/or control of the progression of cancer, tumors, metastases and /or angiogenesis disorders, in combination with radiotherapy and/or with at least one anticancer agent.
HRP20150030AT 2010-07-01 2015-01-12 Pyrazoloquinoline derivatives as dna-pk inhibitors HRP20150030T1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102010025786A DE102010025786A1 (en) 2010-07-01 2010-07-01 Pyrazolochinoline
EP11729377.9A EP2588457B1 (en) 2010-07-01 2011-06-24 Pyrazoloquinoline derivatives as dna-pk inhibitors
PCT/EP2011/003127 WO2012000632A1 (en) 2010-07-01 2011-06-24 Pyrazolo-quinolines

Publications (1)

Publication Number Publication Date
HRP20150030T1 true HRP20150030T1 (en) 2015-03-13

Family

ID=44627920

Family Applications (1)

Application Number Title Priority Date Filing Date
HRP20150030AT HRP20150030T1 (en) 2010-07-01 2015-01-12 Pyrazoloquinoline derivatives as dna-pk inhibitors

Country Status (23)

Country Link
US (1) US8802712B2 (en)
EP (1) EP2588457B1 (en)
JP (1) JP5411393B2 (en)
KR (1) KR101921764B1 (en)
CN (1) CN103080092B (en)
AU (1) AU2011273968B2 (en)
BR (1) BR112012033425A2 (en)
CA (1) CA2804069C (en)
CY (1) CY1115974T1 (en)
DE (1) DE102010025786A1 (en)
DK (1) DK2588457T3 (en)
EA (1) EA022430B1 (en)
ES (1) ES2528447T3 (en)
HK (1) HK1184782A1 (en)
HR (1) HRP20150030T1 (en)
IL (1) IL223872A (en)
MX (1) MX2012014638A (en)
PL (1) PL2588457T3 (en)
PT (1) PT2588457E (en)
RS (1) RS53831B1 (en)
SG (1) SG186870A1 (en)
SI (1) SI2588457T1 (en)
WO (1) WO2012000632A1 (en)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG10201704095UA (en) 2012-04-24 2017-06-29 Vertex Pharma Dna-pk inhibitors
UY34980A (en) * 2012-08-17 2014-03-31 Abbvie Inc NEW INHIBITING COMPOUNDS OF TYPE 10A PHOSPHODIESTERASE
LT2970218T (en) 2013-03-12 2019-03-12 Vertex Pharmaceuticals Incorporated Dna-pk inhibitors
RU2675270C2 (en) 2013-10-17 2018-12-18 Вертекс Фармасьютикалз Инкорпорейтед Co-crystals and pharmaceutical compositions containing same
RU2758669C2 (en) 2016-09-27 2021-11-01 Вертекс Фармасьютикалз Инкорпорейтед Method for treating cancer using combination of dna-damaging agents and dna-pk inhibitors
AU2018206111B2 (en) * 2017-01-09 2022-07-21 Impact Therapeutics (Shanghai), Inc Substituted fused heteroaryl compound serving as a kinase inhibitor, and applications thereof
CN108295070B (en) * 2018-01-08 2020-08-11 华中农业大学 Application of quinoline derivative in preparation of tumor inhibition drug
US11744876B2 (en) 2019-06-10 2023-09-05 Sutro Biopharma, Inc. Immunomodulator antibody drug conjugates and uses thereof
WO2020257235A1 (en) * 2019-06-17 2020-12-24 Sutro Biopharma, Inc. 1-(4-(aminomethyl)benzyl)-2-butyl-2h-pyrazolo[3,4-c]quinolin-4-amine derivatives and related compounds as toll-like receptor (tlr) 7/8 agonists, as well as antibody drug conjugates thereof for use in cancer therapy and diagnosis
KR102663365B1 (en) * 2019-09-25 2024-05-08 한국원자력의학원 Composition for preventing or treating cancer comprising novel trifluoromethylphenylpyrazol derivative
CN114728909A (en) * 2019-09-25 2022-07-08 韩国原子力医学院 Composition for preventing or treating cancer comprising novel trifluoromethylphenylpyrazole derivative as active ingredient

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR930702292A (en) 1990-11-06 1993-09-08 알렌 제이. 스피겔 Quinazolin derivatives for enhancing tumor therapeutic activity
WO2000061186A1 (en) 1999-04-08 2000-10-19 Arch Development Corporation Use of anti-vegf antibody to enhance radiation in cancer therapy
GB0211649D0 (en) * 2002-05-21 2002-07-03 Novartis Ag Organic compounds
EP1648455A4 (en) * 2003-07-23 2009-03-04 Exelixis Inc Anaplastic lymphoma kinase modulators and methods of use
GB0510390D0 (en) 2005-05-20 2005-06-29 Novartis Ag Organic compounds
AU2006276171A1 (en) * 2005-07-22 2007-02-08 Merck Sharp & Dohme Corp. Inhibitors of checkpoint kinases
EP2303890A4 (en) 2008-06-19 2012-04-11 Progenics Pharm Inc Phosphatidylinositol 3 kinase inhibitors
EP2324029A4 (en) * 2008-09-10 2011-09-14 Kalypsys Inc Heterocyclic inhibitors of histamine receptors for the treatment of disease

Also Published As

Publication number Publication date
WO2012000632A1 (en) 2012-01-05
PL2588457T3 (en) 2015-04-30
KR20130041139A (en) 2013-04-24
SG186870A1 (en) 2013-02-28
BR112012033425A2 (en) 2020-08-18
CA2804069C (en) 2018-06-12
SI2588457T1 (en) 2015-03-31
CN103080092A (en) 2013-05-01
KR101921764B1 (en) 2018-11-23
RS53831B1 (en) 2015-06-30
US8802712B2 (en) 2014-08-12
EA201300073A1 (en) 2013-11-29
EP2588457B1 (en) 2014-11-05
IL223872A (en) 2016-02-29
ES2528447T3 (en) 2015-02-10
CN103080092B (en) 2014-12-17
CA2804069A1 (en) 2012-01-05
PT2588457E (en) 2015-02-05
JP5411393B2 (en) 2014-02-12
AU2011273968B2 (en) 2014-11-20
CY1115974T1 (en) 2017-01-25
US20130150359A1 (en) 2013-06-13
JP2013531663A (en) 2013-08-08
MX2012014638A (en) 2013-02-07
DE102010025786A1 (en) 2012-01-05
EA022430B1 (en) 2015-12-30
DK2588457T3 (en) 2015-01-12
EP2588457A1 (en) 2013-05-08
AU2011273968A1 (en) 2013-02-14
HK1184782A1 (en) 2014-01-30

Similar Documents

Publication Publication Date Title
HRP20150030T1 (en) Pyrazoloquinoline derivatives as dna-pk inhibitors
HRP20150489T1 (en) Imidazo[4,5-c]quinolines as dna-pk inhibitors
JP6862495B2 (en) Treatment of B-cell malignancies with a combination of JAK and PI3K inhibitors
HRP20160495T1 (en) Morpholinyl benzotriazine for use in cancer therapy
HRP20220886T1 (en) Compositions and methods for the production of pyrimidine and pyridine compounds with btk inhibitory activity
EP2650293A8 (en) [1,2,4]triazolo[4,3-b][1,2,4]triazine compound, preparation method and use thereof
CU20110217A7 (en) AMINO-PROPIONIC DERIVATIVES REPLACED AS NEPRILISINE INHIBITORS
MX2009009843A (en) Spiro substituted compounds as angiogenesis inhibitors.
JP2013529196A5 (en)
EA201290237A1 (en) KINASE INHIBITORS
AR078157A1 (en) DERIVATIVES OF PIRAZOL- [4,5-D] PIRROLO [2,3-B] PYRIDINE INHIBITORS OF JAK 2 THYROSINQUINASES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEMSELVES AND USE OF THE SAME IN THE TREATMENT OF CANCER
JP2014503567A5 (en)
CL2008003810A1 (en) Compounds derived from 5-anilino imidazole [1,5-a] pyridine or pyrazine, inhibitors of mek kinase activity; pharmaceutical compositions containing them; and its use to treat hyperproliferative disorders and an inflammatory disease.
HRP20131021T1 (en) Novel 7-deazapurine nucleosides for therapeutic uses
US20190040063A1 (en) Tricyclic compound for bromodomain-containing protein inhibitor and preparation pharmaceutical composition, and application thereof
HRP20211801T1 (en) Quinolin-2-one derivatives
AR063869A1 (en) TUMORS RADIOSENSIBILIZATION METHOD USING A RADIOSENSIBILIZING AGENT
AR119322A1 (en) COMPOUNDS DERIVED FROM 1H-PYRIDO[1,2-A]PYRAZINE AS MAGL INHIBITORS
EP4110782A1 (en) Compounds as cdk2/4/6 inhibitors
HRP20210095T1 (en) Novel amino-imidazopyridine derivatives as janus kinase inhibitors and pharmaceutical use thereof
SI3087076T1 (en) Imidazopyrazinone derivatives
HRP20120979T1 (en) Pyridazinone derivatives
JP2015502371A5 (en)
SI3174881T1 (en) (1,2,4)triazolo(4,3-b)pyridazines for use in the treatment of proliferative diseases
EA202190036A1 (en) CRYSTALLINE FORM OF THE COMPOUND FOR INHIBITING CDK4 / 6 ACTIVITY AND ITS APPLICATION